Arthritis is a form of joint disorder that involves inflammation of one or more joints. There are over 100 different forms of arthritis. The most common form, osteoarthritis (degenerative joint disease), is a result of trauma to the joint, infection of the joint, or age. Other arthritis forms are rheumatoid arthritis, psoriatic arthritis, and related autoimmune diseases. Septic arthritis is caused by joint infection. The major complaint by individuals who have arthritis is joint pain. Pain is often a constant and may be localized to the joint affected. The pain from arthritis is attributed to multiple factors including inflammation that occurs around the joint, damage to the joint from disease, daily wear and tear of joint, muscle strains caused by forceful movements against stiff painful joints, and fatigue.
Osteoarthritis (OA) is the most common form of arthritis. In mammals, it can affect both the larger and the smaller joints of the body, including the hands, wrists, feet, back, hip, and knee. The disease is essentially one acquired from daily wear and tear of the joint; however, OA can also occur as a result of injury. OA begins in the cartilage and eventually causes the two opposing bones to erode into each other. Initially, the condition starts with minor pain during activities, but as the disease progresses the pain can be continuous and even occur while in a state of rest. The pain can be debilitating and prevent one from doing some activities. OA typically affects the weight-bearing joints, such as the back, spine, and pelvis.
Unlike rheumatoid arthritis, OA is most commonly a disease of the elderly. Disease onset is gradual and usually begins after the age of 40. More than 30% of women have some degree of OA by age 65. One in two people in the U.S. will experience some form of OA in their lifetime. OA is much more common in women than men and it accounts for more than 50% of arthritis cases in the U.S. (nearly 27 million of the 46 million adults).
OA cannot be cured, but one can prevent the condition from worsening. Pain medications are widely required by individuals with osteoarthritis. Such medications include analgesics such as acetaminophen and NSAIDs (non-steroidal anti-inflammatory drugs). These medications have side effects, which may be serious in some patients. As a result, patients often rely upon natural products with the hope that they are safer than allopathic medications.
Among natural products used for relief of OA symptoms, glucosamine and chondroitin have the longest stay in the market, despite doubts about their efficacy. A major OA clinical trial on glucosamine and chondroitin was the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT, ClinicalTrials.gov NCT00032890 Glucosamine/Chondroitin Arthritis Intervention Trial). GAIT was funded by National Institutes of Health to test the effects of chondroitin and glucosamine on OA of the knee. This multicenter, placebo-controlled, double-blind, six-month-long trial found that glucosamine plus chondroitin had no statistically significant effect on symptoms of OA in the overall group of OA patients. However, in the moderate-to-severe pain subgroup, the combination of chondroitin and glucosamine was found to be subjectively more effective (in 25% of the patients) in treating pain than celecoxib or chondroitin and glucosamine taken individually. Due to small sample sizes in the sub-group (roughly 250 people), the researchers concluded that this finding needs further validation. The study also found chondroitin sulfate to have no significant effect in reducing joint swelling, effusion, or both. These results indicate that glucosamine and chondroitin do not effectively relieve OA pain in the overall group of osteoarthritis patients, though it may be an effective treatment for those suffering from moderate-to-severe pain.
In a follow-up study (New England Journal of Medicine (2006) 354 (8): 795-808), 572 patients from the GAIT trial continued the supplementation for 2 years. After 2 years of supplementation with glucosamine and chondroitin sulfate, alone or in combination, there was no benefit in slowing the loss of cartilage, in terms of joint space width, when compared to a placebo. Further, in another 2-year follow-up study, there was no significant pain reduction or improved function when compared to a placebo. In addition, glucosamine and chondrotin are produced from crustacean exoskeletons and cartilage, respectively, which may pose a problem for vegetarians and those who are allergic to crustaceans.
Another product recently introduced in the market for relief from OA is undenatured type 2 collagen, which is obtained from chicken cartilage (Int. J. Med. Sci. (2009) 6(6): 312-321). Again, vegetarians may have a problem with the source of this product.
Thus, there is a need for a safe and efficacious vegetarian product for treatment of OA. A possible candidate is Terminalia chebula Retz. (Combritaceae), (“TC”), which has been extensively used in Ayurveda, Unani and Homoeopathic systems of medicine for improvement of different health conditions, e.g., constipation, diarrhoea, ulcers, gastroenteritis, asthma, cough, dyspnea, dyspepsia, hemorrhoids, candidiasis, parasites, malabsorption syndrome, hepatomegaly, vesicular and renal calculi, urinary discharges, tumors, skin diseases, leprosy, intermittent fever, rheumatoid arthritis, gout, neuropathy, paralysis, memory loss, epilepsy, depression, leucorrhea, diabetes, cardiovascular diseases, anorexia, and wounds, among others (B. Das, Materia Medica of Ayurveda (New Delhi: B. Jain Publishers, 1991), p. 8; K. R. Kirtikar and B. D. Basu, “Terminalia chebula.” In: Indian Medicinal Plants, (2nd Edn., Allahabad, India: Lolit Mohan Basu Publication, 1935), pp. 1020-23; and P. V. Sharma, Dravya Guna Vigyana (Vol. 2, Varanasi: Chaukhamba Bharati Academy, 1995), pp. 753-58). T. chebula fruit and its different solvent extractives were reported to exhibit hepatoprotective, cardioprotective, antimutagenic/anticarcinogenic, cytoprotective, radioprotective, antioxidant and adaptogenic, antimicrobial, antifungal, antiviral, antiamoebic, immunomodulatory, antidiabetic, wound healing, antispasmodic, and purgative activities in various animal models (S. S. Tasduq, et al., Human and Exp. Toxicol. (2006) 25: 11-18; H. Y. Cheng, et al., Biol. Pharm. Bull. (2003) 26:1331-5; S. Kaur, et al., Mutagen Res. (1998) 419: 169-79; Suthienkul, et al., South-East Asian Journal Trop. Med., Public Health (1993) 24: 751-5; Ahmad, et al., J. Ethnopharmacol. (1998) 62: 183-93; and N. K. Rao, et al., BMC Complement. Altern. Med. (2006) 6: 127-32).
Several animal studies have been carried out to determine the effects of alcoholic/hydro-alcoholic extracts of T. chebula on rheumatoid arthritis. Jong Bae Seo, et. al. (Biomol. Therapeut. (Seoul) (2012) January; 20(1): 104-112) studied the effect of an alcoholic extract of T. chebula on collagen-induced arthritis in mice and concluded that T. chebula extract can be a therapeutic candidate for treatment of rheumatoid arthritis. Nair, et. al. (J. Pharm. Pharmacol. (2010) December; 62(12):1801-6) studied the effect of an hydro-alcoholic extract of T. chebula in rats and concluded that this extract has the potential to be used as a disease-modifying agent in rheumatoid arthritis. Kim, et. al. (Acta Pol. Pharm. (2010) March-April; 67(2):145-50) studied 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG), a bioactive compound derived from a methanolic extract of T. chebula, on rabbit articular chondrocytes in vitro and reported that type II collagen expression was induced. Kim, et. al. hypothesized that this compound derived from TC might be beneficial in relieving painful joint conditions.
Although animal models are more suited for studying the effect of drugs in rheumatoid arthritis, animal studies for OA do not necessarily predict the efficacy of a product in human beings. A. M. Bendele (J. Musculoskelet. Neuronal Interact. (2001) June; 1(4):363-76) discussed various animal models for osteoarthritis study and concluded that none of these models have a proven track record of proving efficacy in human disease. W. B. van den Berg (Current Opinion in Rheumatology (2001) 13(5):452-456), working with transgenic murine OA models concluded that treatment with a range of disease-modifying drugs showed some efficacy in a number of OA models, but its predictive value for human OA remains obscure. Christopher B. Little and Margaret M. Smith (Current Rheumatology Reviews (2008) 4(3): 1-8) opined that none of the animal models of OA is truly predictive for humans, although valuable for discovery purposes. As per Kenneth D. Brandt (Biorheology (2002) Vol. 39, Number 1-2, pp. 221-235), animal models have proved to be of considerable importance in elucidating mechanisms underlying joint damage in osteoarthritis (OA) and providing proof of concept in the development of pharmacologic and biologic agents that may modify structural damage in the OA joint, but the utility of animal models in predicting the response to an intervention with a drug or biologic agent in humans, however, can be established only after evidence is obtained of a positive effect of the agent in humans.
In addition, not all of the TC extracts available in the market are effective because of the absence of certain bioactives—e.g., chebulinic acid and chebulagic acid due to non-optimized extraction processes.
Thus, it is recommended to study an extract of Terminalia chebula, optimized to contain the maximum percentages of chebulinic acid and chebulagic acids in humans before asserting its effectiveness in osteoarthritis in humans. The present invention is based on a human clinical study of an optimized extract of Terminalia chebula in patients with moderate osteoarthritis.
If a way could be found to treat or prevent the symptoms associated with osteoarthritis using an extract of Terminalia chebula in individuals this would represent a contribution to the medical and nutraceutical arts. Further, if a way could be found to treat or prevent the symptoms associated with osteoarthritis using an aqueous extract of Terminalia chebula, for example joint pain, this would represent a valuable contribution to the art.